There are many disorders characterized by circulatory system problems:
Peripheral Vascular Disease
The circulatory system consists of two types of blood vessels, arteries and veins, which carry the blood throughout the body. Arteries carry oxygen- and nutrient-rich blood from the heart to the organs and cells. Among both arteries and veins, central blood vessels are those leading directly to or from the heart, and peripheral blood vessels are those in the feet, legs, lower abdomen, arms, neck or head. Veins carry oxygen-depleted blood and wastes through the kidneys, liver, and lungs, where wastes are filtered out and removed from the body. The venous blood is then again filled with oxygen in the lungs and returned back to the heart. The two types of blood vessels are interconnected by small web-like vessels called capillaries.
The term peripheral vascular disease (PVD) refers to damage, dysfunction or obstruction within peripheral arteries and veins. Peripheral artery disease (PAD) is the most common form of PVD.
Peripheral vascular disease is the most common disease of the arteries and is a very common condition in the United States. It occurs mostly in people older than 50 years. Peripheral vascular disease is a leading cause of disability among people older than 50 years, as well as in those people with diabetes.
About 10 million people in the United States have peripheral vascular disease, which translates to about 5% of people older than 50 years. The number of people with the condition is expected to grow as the population ages. Men are slightly more likely than women to have peripheral vascular disease.
There are two types of peripheral vascular disease. The first type is peripheral arterial disease (PAD), which refers to diseased peripheral arteries. Peripheral artery disease is often named after the artery that is affected.    Carotid artery disease. Narrowing of one or more carotid arteries in the neck, which supply oxygen-rich blood to the brain, through atherosclerosis.    PAD of the lower extremities (legs). Narrowing of one or more arteries in the leg (usually the femoral artery near the groin).    PAD of the renal arteries. Narrowing of one or more renal arteries, leading to the kidneys.    Abdominal aortic aneurysm (AAA). The bulging or ballooning out of part of the wall of the abdominal section of the aorta, the body's main artery that carries oxygen-rich blood from the heart to the body.    Raynaud's phenomenon is a condition that affects the blood vessels in the extremities—generally, the fingers and toes. It is characterized by episodic attacks, called vasospastic attacks, in which the blood vessels in the digits (fingers and toes) constrict (narrow), usually in response to cold temperatures and/or emotional stress. When this condition occurs on its own, it is called primary Raynaud's phenomenon. When it occurs with another condition such as scleroderma or lupus, it is called secondary Raynaud's phenomenon.    Buerger disease. A rare type of peripheral arterial disease that involves inflammation of the smaller arteries in the extremities and gets worse over time, causing increasing pain in the legs (claudication). Buerger's disease, also called thromboangitis obliterans, is a rare disease of the arteries and veins in the arms and legs. Buerger's disease is characterized by a combination of inflammation and clots in the blood vessels, which impairs blood flow. This eventually damages or destroys tissues and may lead to infection and gangrene. Buerger's disease usually begins in the hands and feet and may progress to affect larger areas of the limbs.    Polyarteritis nodosa (PN). A rare and potentially deadly form of vasculitis, a condition in which small to medium-sized blood vessels (usually arteries) are abnormally inflamed. PN causes structural damage to the inside walls of the inflamed blood vessels, which reduces the flow of blood.
The second type of peripheral vascular disease is peripheral venous disorders, which refer to problems in the peripheral veins. There are a number of different peripheral venous disorders, which include:    Phlebitis. Inflammation of the vein.    Thrombophlebitis (including superficial vein thrombosis and deep vein thrombosis). An obstructing blood clot (a thrombus) has formed, causing the surrounding veins to become inflamed (phlebitis).    Varicose veins. Abnormally widened veins that are swollen, dark and frequently twisted or contorted instead of straight. They usually occur in the legs and may cause swelling (edema), inflammation and a dark color around the ankles.    Chronic venous insufficiency. An advanced stage of leg vein disease in which the veins become incompetent, causing blood to pool in the legs and feet, and sometimes to leak backwards.
The most common cause of peripheral vascular disease is atherosclerosis. Atherosclerosis is a gradual process in which a material called plaque builds up inside the arteries. This material is a mixture of lipids, calcium, scar tissues, and other substances which harden slightly, forming the plaques (sometimes called lesions). Atherosclerosis is frequently called arteriosclerosis, or just plain “hardening of the arteries.” Atherosclerosis can reduce blood flow, in particular, it can reduce blood flow to various parts of the body including the extremities, the heart, or to the brain. Once the atherosclerotic plaques form, they block, narrow, or weaken the vessel walls.
When an artery is blocked or narrowed, the part of the body supplied by that artery does not get enough blood/oxygen. The lack of blood flow in the extremities such as the leg or foot can be detected by measuring the blood pressure in several places. An ankle/brachial index has been defined as a way to classify this type of blood flow. The ankle/brachial index (ABI) is the ratio of the blood pressure at the ankle to that in the upper arm. A value greater than or equal to 1.0 of the ABI suggests that blood flow is normal in the limbs, and a value less than 1.0 suggests otherwise (diabetics with PVD can have ABI values of greater than 1). A lack of blood flow to the extremities then leads to a lack of oxygen getting to the tissues, and this is known as ischemia.
PVD can be due to other causes besides atherosclerosis. These include the following:    Blood clot: A blood clot can block a blood vessel (thrombus/embolus).    Diabetes: One of the complications of diabetes is PVD.    Inflammation of the arteries: This condition is called arteritis and can cause narrowing or weakening of the arteries.    Infection: The inflammation and scarring caused by infection can block, narrow, or weaken blood vessels. Both salmonellosis (infection with Salmonella bacteria) and syphilis are two infections traditionally known to infect and damage blood vessels.    Structural defects: Defects in the structure of a blood vessel can cause narrowing. Most of these cases are acquired at birth. Takayasu disease is a vascular disease affecting the upper vessels of the body and affects usually Asian females.    Injury: Blood vessels can be injured in an accident such as a car wreck or a bad fall.
Only about one-half of the individuals with peripheral vascular disease have symptoms. Almost always, symptoms are caused by the leg muscles not getting enough blood. Whether there are symptoms depends partly on which artery is affected and to what extent blood flow is restricted.
The most common symptom of peripheral vascular disease in the legs is pain in one or both calves, thighs, or hips. The pain usually occurs while walking or climbing stairs and stops during rest. Such a pain is called intermittent claudication. It is usually a dull, cramping pain. It may also feel like a heaviness, tightness, or tiredness in the muscles of the legs.
Cramps in the legs have several causes, but cramps that start with exercise and stop with rest most likely are due to intermittent claudication. When the blood vessels in the legs become even more blocked, leg pain at night is very typical, and the individual almost always hangs his or her feet down to ease the pain. Hanging the legs down allows for blood to passively flow into the distal part of the legs.
Other symptoms of peripheral vascular disease include the following:
Buttock pain
Numbness, tingling, or weakness in the legs
Burning or aching pain in the feet or toes while resting
A sore on a leg or a foot that will not heal
One or both legs or feet feel cold or change color (pale, bluish, dark reddish)
Loss of hair on the legs
Impotence
Having symptoms while at rest is a sign of more severe disease.
A therapy currently used to treat the ischemia of PVD is to have the patient breathe enriched oxygen, frequently under pressure such as in hyperbaric oxygen therapy (HBOT). One method for doing this employs 100% oxygen at 1.3-1.4 atmospheres pressure.
Coronary Artery Disease
Coronary artery disease (CAD) occurs when the arteries that supply blood to the heart muscle (the coronary arteries) become narrowed. The arteries narrow due to buildup of a material called plaque from atherosclerosis on their inner walls. As the plaque increases, the insides of the coronary arteries get narrower and less blood can flow through them. Eventually, blood flow to the heart muscle is reduced, and, because blood carries much-needed oxygen, the heart muscle is not able to receive the amount of oxygen it needs. Reduced or cutoff blood flow and oxygen supply to the heart muscle can result in:
Angina. Angina is chest pain or discomfort that occurs when the heart does not get enough blood.
Heart attack. A heart attack happens when a blood clot develops at the site of plaque in a coronary artery and suddenly cuts off most or all blood supply to that part of the heart muscle. Cells in the heart muscle begin to die if they do not receive enough oxygen-rich blood. This can cause permanent damage to the heart muscle.
Over time, CAD can weaken the heart muscle and contribute to:
Heart failure. In heart failure, the heart can't pump blood effectively to the rest of the body. Heart failure does not mean that the heart has stopped or is about to stop. Instead, it means that the heart is failing to pump blood the way that it should.
Arrhythmias. Arrhythmias are changes in the normal beating rhythm of the heart. Some can be quite serious.
CAD is the most common type of heart disease. It is the leading cause of death in the United States in both men and women.
Embolism
Blood flow decreases due to a thrombus or embolism. An embolism occurs when an object (the embolus, plural emboli) migrates from one part of the body (through circulation) and cause(s) a blockage (occlusion) of a blood vessel in another part of the body. This can be contrasted with a “thrombus” which is the formation of a clot within a blood vessel, rather than being carried from somewhere else.
Blood clots form the most common embolic material by far: other possible embolic materials include fat globules (a fat embolism), air bubbles (an air embolism), talc embolism (often following drug abuse), septic emboli (containing pus and bacteria), atherosclerotic emboli, or amniotic fluid. Emboli often have more serious consequences when they occur in the so-called “end-circulation” areas of the body that have no redundant blood supply, such as the brain, heart, and lungs.
Assuming a normal circulation, a thrombus or other embolus formed in a systemic vein frequently impact in the lungs, after passing through the right side of the heart. This forms a pulmonary embolism that can be a complication of deep-vein thrombosis.
Some congenital abnormalities of the circulation, especially septal defects (holes in the cardiac septum), allow an embolus from a systemic vein to cross into the arterial system and land anywhere in the body. The most common such abnormality is patent foramen ovale, occurring in about 25% of the adult population, but here the defect functions as a valve which is normally closed, because pressure is slightly higher in the left side of the heart. In unfortunate circumstances, e.g. if patient is coughing just when an embolus is passing, passage to the arterial system may occur.
Emboli starting in the heart (from a thrombus in the left atrium secondary to atrial fibrillation or septic emboli from endocarditis) can cause emboli in any part of the body. An embolus landing in the brain from either the heart or a cerebral artery will likely cause an ischemic stroke.
Embolism of cardiac origin is also frequently encountered in clinical practice. Thrombus formation within the atrium in valvular disease occurs mainly in patients with mitral valve disease, and especially in those with mitral valve stenosis with atrial fibrillation (AF). In the absence of AF, pure mitral regurgitation has low incidence of thromboembolism. Absolute risk of emboli in idiopathic AF depends on other risk factors such as increasing age, hypertension, diabetes, recent heart failure, or previous stroke. Thrombus formation can also take place within the ventricles, and it occurs in approximately 30% of anterior wall myocardial infarctions, compared to only 5% of inferior ones. Other risk factors include poor ejection fraction (<35%), size of infarct, as well as presence of AF. In the first three months after infarction, left ventricle aneurysms have 10% risk of embolization. Patients with prosthetic valves also carry a significant increase in risk of thromboembolism. Risk varies on the valve type (bioprosthetic or mechanical), the position (mitral or aortic), and presence of other factors such as AF, left ventricular dysfunction, previous emboli, etc.
Brain Ischemia
A stroke is associated with a reduced blood flow in the brain. A stroke can be caused by either a clot or a ruptured blood vessel in the brain.
Neurological researchers have been searching for a way to prevent ischemic injury to a brain that is exposed to a lowered oxygen situation. In addition, a primary complication of many types of invasive surgery is hypoxic cell injury (ie., injury to cells due to periods of low oxygen). Common surgical procedures, such as those involving vascular clamping and/or manipulation of cardiac function, entail substantial risk for such injury. The risk of tissue damage resulting from low oxygen is greatest in the nervous system, where the metabolic demands of neurons are extremely high. For example, after coronary artery bypass surgery, some form of cognitive deficit has been reported to occur in many patients.
A transient ischemic attack (TIA) is a “mini-stroke” caused by temporary disturbance of blood supply to an area of the brain, which results in a sudden, brief decrease in brain function. In a TIA, the blood supply is only temporarily blocked. For example, a blood clot may dissolve and allow blood to flow normally again. A TIA is different than a small stroke. The symptoms of TIAs go away in less than 24 hours, usually less than one hour. TIAs do not show lasting changes on CT or MRI scans. Small strokes do show changes on such tests.
In general, therapeutic strategies targeting ischemic injury can be classified by when they are administered: preischemic, intraischemic, and postischemic. A preischemic therapeutic intervention can be thought of as inducing tolerance in the tissues. Such an intervention can also be thought of as providing protection, such as neuroprotection for the brain. Such therapy is sometimes given just prior to an ischemic or hypoxic challenge, but it can also be given earlier than that. If a conditioning stimulus is given several days prior to the injury, it can induce what is called “delayed tolerance” (or “late tolerance”). Some stimuli known to do this are hypoxia, hypothermia, long-term hyperbaric oxygen, and cytokines, among others.
One way to test whether or not a pretreatment therapy induces tolerance or protection in brain tissue is to conduct stroke research. In this research, vessels are tied off so that blood flow to the brain of the animals is greatly reduced, and this induces a stroke. The region of the brain affected by the stroke consists of the ischemic core and the surrounding affected tissue (called the penumbra). By measuring the volumes of those regions it is possible to evaluate the effectiveness of a therapy in inducing tolerance in the brain.
Ischemic Osteonecrosis
Ischemic osteonecrosis means, literally, “dead bone from poor blood flow.” It may have either dead bone or bone marrow that has been slowly strangulated or nutrient-starved. Bone with chronically poor blood flow develops either a fibrous marrow (fibers can live in nutrient starved areas), a greasy, dead fatty marrow (“wet rot”), a very dry, sometimes leathery marrow (“dry rot”), or a completely hollow marrow space (“cavitation”). Any bone can be affected, but the hips, knees and jaws are most often involved. Pain is often severe but about ⅓ of patients do not experience pain.
Chronic Ocular Disease
Reduced capillary blood flow may be of consequence in the progression of chronic ocular diseases such as glaucoma.
Macular Degeneration
Macular degeneration, often called AMD or ARMD (age-related macular degeneration), is the leading cause of vision loss and blindness in Americans aged 65 and older. Because older people represent an increasingly larger percentage of the general population, vision loss associated with AMD is a growing problem.
AMD occurs with degeneration of the macula, which is the part of the retina responsible for the sharp, central vision needed to read or drive. Because the macula primarily is affected in AMD, central vision loss may occur. The disease is marked by new blood vessels growing into the eyes.
Diabetic Retinopathy
Diabetic retinopathy is a potentially blinding complication of diabetes that damages the eye's retina. It affects half of all Americans diagnosed with diabetes. Diabetic retinopathy occurs when diabetes damages the tiny blood vessels in the retina. Some people with diabetic retinopathy develop a condition called macular edema. As the disease progresses, it enters its advanced, or proliferative, stage. Fragile, new blood vessels grow along the retina and in the clear, gel-like vitreous humor that fills the inside of the eye. Without timely treatment, these new blood vessels can bleed, cloud vision, and destroy the retina.
Carotenoids are a class of hydrocarbons consisting of isoprenoid units joined in such a manner that their arrangement is reversed at the center of the molecule. The backbone of the molecule consists of conjugated carbon-carbon double and single bonds, and can also have pendant groups.
Crocetin has been shown to cause a reduction in atherosclerotic plaque formation over time in rabbits (Gainer, J. L. and Chisolm, G. M., Oxygen diffusion and atherosclerosis. Atherosclerosis, 19: 135-138, 1974).
U.S. Pat. No. 6,060,511 relates to trans sodium crocetinate (TSC) and its uses. The patent covers various uses of the TSC such as improving oxygen diffusivity and treatment of hemorrhagic shock.
U.S. patent application Ser. No. 10/647,132 relates to synthesis methods for making bipolar trans carotenoid salts (BTC) and methods of using them.
U.S. patent application Ser. No. 11/361,054 relates to improved BTC synthesis methods and novel uses of the BTC.
U.S. Provisional Patent application Ser. No. 61/001,095 relates to a class of therapeutics that enhance small molecule diffusion.